RNA plays a critical role in a host of diseases and thus can serve as an important drug target. The vast majority of RNA targets, however, have not been utilized in targeting endeavors. This is due to a lack of information on the RNA motifs that bind small molecules, such motifs are internal and hairpin loops, for example. The overall goal of our proposed research is to utilize MLPCN resources to identify small molecules that specifically bind to the repeating 1x1 nucleotide AA internal loops that are present in the expanded r(CAG) repeats that cause Huntington's Disease (HD) and Spinocerebellar Ataxia Type 3 (SCA3), which have no known cures. We propose to complete MLPCN screens using a dye-displacement assay in which fluorescence emission increases when a small molecule binds to an RNA target and displaces the dye. This approach has been validated using the LOPAC library and the NIH clinical collection; thus, it is well suited for a HTS campaign. Identified ligands will then be tested in a variety of secondary assays. Specifically, leads will be tested fo: a.) RNA binding selectivity; b.) displacement of proteins that bind the triplet-repeating transcripts; c.) correction of pre-mRNA splicing defects; and d.) inhibition of translation of mutat Huntington, which is the causative agent in HD.